The subject of the invention is novel 9-substituted-5-carboxy-oxadiazino-quinolone derivatives, their preparation and their application as anti-bacterials.
9-substituted-5-carboxy-oxadiazino-quinolone derivatives have been described in various patents, applications or publications and there may be cited for example: EP 0259804, EP 0343524, EP 0688772, EP 0394553, EP 0470252, U.S. Pat. No. 4,990,517, U.S. Pat. No. 5,480,879, U.S. Pat. No. 5,679,675, or also J. Med. Chem. 1996, 39, 3070-3088, J. Med. Chem. 2002, 45, 5564-5575, or J. Med. Chem. 2004, 47, 2097-2109. In particular, EP 0394553 and EP 0470252 describe quinolone derivatives substituted by a piperazine ring bearing substituents which can form a spiro ring.
An object of the invention is the compounds of formula (I):
in which:                either R1 and R2 form a 5 or 6 membered carbon cycle optionally substituted by a group Ra and/or by two groups Rb and R′b fixed on the same carbon atom, Ra represents hydrogen, halogen, (C1-C6) linear or branched alkyl, (C3-C6) cyclic alkyl, (C6-C10) aryl, (C7-C12) aralkyl, OH, (C1-C6) linear or branched alkoxy, O—(C6-C10) aryl, O—(C7-C12) aralkyl or NRR′, R and R′, represent together a (C3-C6) carbon chain possibly interrupted by an heteroatom selected from N, O and S and optionally substituted by 1 or 2 (C1-C6) linear or branched alkyls, or R and R′, identical or different, represent hydrogen, (C1-C6) linear or branched alkyl, (C3-C6) cyclic alkyl or R represents hydrogen and R′ represents a 5 or 6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, optionally substituted by 1 or 2 (C1-C6) linear or branched alkyls, Rb and R′b, identical or different, represent hydrogen, (C1-C6) linear or branched alkyl, (C3-C6) cyclic alkyl, (C6-C10) aryl or (C7-C12) aralkyl, or Rb and R′b form together a carbonyl;        or R1 represents a CO—R′1 radical, wherein R′1 represents a 5 or 6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, optionally substituted by 1 or 2 (C1-C6) linear or branched alkyls, and R2 represents hydrogen;        or R1 represents a radical of formula:        
wherein Rc represents a (C1-C6) linear or branched alkyl, optionally substituted by a member of the group constituted by COOH, COORf, NH2, NH(C1-C6) linear or branched alkyl, N(C1-C6) di-linear or branched alkyl and NH—CO(C1-C6) linear or branched alkyl, Rf represents a (C1-C6) linear or branched alkyl, Rd represents hydrogen or CO—(C1-C6) linear or branched alkyl and Re represents hydrogen, or Rc and Re form a pyrrolidine ring, and Rd is defined as above, and R2 represents hydrogen;                or R1 represents a radical of formula:        
wherein R″1 represents a (C1-C6) linear or branched alkyl substituted by COOH, COORf, Rg or CORg, Rf is defined as above, Rg represents a morpholino, thiomorpholino or piperazino group possibly substituted by a (C1-C6) linear or branched alkyl or Rg represents phenyl optionally substituted by 1 to 3 members of the group constituted by halogen, CF3, (C1-C6) linear or branched alkyl and (C1-C6) linear or branched alkoxy, or Rg represents a 5 or 6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, optionally substituted by 1 or 2 (C1-C6) linear or branched alkyls, and R2 represents hydrogen;                R3 represents hydrogen, —(CH2)m—NRR′, —(CH2)m—OR, (C1-C6) linear or branched alkyl, (C3-C6) cyclic alkyl, or R3 represents (C6-C10) aryl or (C7-C12) aralkyl or a 5 or 6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, all being possibly substituted by halogen, CF3, (C1-C6) linear or branched alkyl and (C1-C6) linear or branched alkoxy, m is 0, 1 or 2 and R and R′ are defined as above and R′3 represents hydrogen,or R3 and R′3 represent (C1-C6) linear or branched alkyl or form together a (C3-C6) spiro ring;        R4 and R′4, identical or different, represent hydrogen or (C1-C6) linear or branched alkyl optionally substituted by 1 to 3 halogens or R4 represents a (C1-C6) linear or branched alkoxy carbonyl group and R′4 represents hydrogen;        R5 represents methyl optionally substituted by one to three halogens;        R6 represents hydrogen, (C1-C6) linear or branched alkyl or (C7-C12) aralkyl;        R7 represents hydrogen, fluorine, NO2, CF3 or CN;in the form of mixtures of enantiomers or single enantiomers,as well as their addition salts with mineral and organic acids and their salts with mineral or organic bases.        
The compounds of the invention have remarkable antibacterial properties which make them particularly indicated for use as medicaments in both human and veterinary medicine. In general formula (I) and hereafter:                by 5 or 6 membered heterocycle is meant an aromatic or non aromatic heterocycle and, for example, a pyrrole, furane, thiophene, pyrazole, triazole, tetrazole, thiazole, isothiazole, thiadiazole, imidazole, isoxazole, furazane, pyridine, pyrazine or pyridazine ring, the substituents being fixed, whenever possible, at any possible position, including on a nitrogen atom;        by (C1-C6) linear or branched alkyl is meant any possible radical and in particular methyl, ethyl, propyl or isopropyl, butyl, isobutyl, tert-butyl or isopentyl;        by (C3-C6) cyclic alkyl radical is meant any possible radical, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;        by linear or branched (C1-C6) alkoxy is meant any possible radical and in particular methoxy, ethoxy, propoxy or isopropoxy, butoxy, isobutoxy or tert-butoxy;        by (C6-C10) aryl is meant phenyl or naphthyl, and preferably phenyl;        by (C7-C12) aralkyl is meant preferably benzyl or phenethyl;        the above aryl and aralkyl can be substituted by halogen, CF3, (C1-C6) linear or branched alkyl and (C1-C6) linear or branched alkoxy;        by halogen in formula (I) and above is meant fluorine, chlorine, bromine or iodine, and preferably fluorine or chlorine.        
Among the acid salts of the products of formula (I), there may be cited, among others, those formed with mineral acids, such as hydrochloric, hydrobromic, hydroiodic, sulphuric or phosphoric acid or with organic acids such as formic, acetic, trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic acids, such as methanesulphonic and ethanesulphonic acids, arylsulphonic acids such as benzenesulphonic and paratoluenesulphonic acids. Among the base salts of the products of formula (I), there may be cited, among others, those formed with mineral alkalis such as, for example, sodium, potassium, lithium, calcium, magnesium or ammonium hydroxide or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, piperidine, piperazine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine. Among the preferred compounds of formula (I) according to the invention are those wherein R4, R′4 and R6 represent hydrogen, R5 represents methyl, and R7 represents fluorine.
A preferred object of the invention is the compounds of formula (I) as defined above, in which R1 and R2 form a 5 or 6 membered carbon cycle optionally substituted as defined above, R3 and R′3, R4 and R′4, R5, R6 and R7 being defined as above, in the form of mixtures of enantiomers or single enantiomers, as well as their addition salts with mineral and organic acids and their salts with mineral or organic bases. An especially preferred object of the invention is the compounds of formula (I) as defined above, in which R1 and R2 form a 5 membered carbon cycle optionally substituted as defined above, R3 and R′3, R4 and R′4, R5, R6 and R7 being defined as above, in the form of mixtures of enantiomers or single enantiomers, as well as their addition salts with mineral and organic acids and their salts with mineral or organic bases.
Within these preferred compounds one can especially mention those having the following formula (I1)
wherein Ra, Rb and R′b, R3 and R′3 are defined as above.
Another preferred object of the invention is the compounds of formula (I) as defined above, in which R1 represents a CO—R′1 radical, wherein R′1 represents a 5 or 6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, optionally substituted by 1 or 2 (C1-C6) linear or branched alkyls, and R2 represents hydrogen,
in the form of mixtures of enantiomers or single enantiomers, as well as their addition salts with mineral and organic acids and their salts with mineral or organic bases.
Another preferred object of the invention is the compounds of formula (I) as defined above, in which R1 represents a radical of formula:
wherein R″1 represents a (C1-C6) linear or branched alkyl radical substituted by COOH, COORf, Rg or CORg, Rf represents a (C1-C6) linear or branched alkyl,
Rg represents morpholino, thiomorpholino or piperazino group, possibly substituted by a (C1-C6) linear or branched alkyl radical or Rg represents phenyl optionally substituted by 1 to 3 members of the group constituted by halogen, CF3, (C1-C6) linear or branched alkyl and (C1-C6) linear or branched alkoxy, or Rg represents a 5 or 6 membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, optionally substituted by 1 or 2 (C1-C6) linear or branched alkyls, and R2 represents hydrogen,
in the form of mixtures of enantiomers or single enantiomers, as well as their addition salts with mineral and organic acids and their salts with mineral or organic bases.
Among the compounds of the invention, there may be cited the compounds described in the experimental part, in particular those whose names follow:    8-Fluoro-3-methyl-9-(octahydro-pyrido[1,2-a]pyrazin-2-yl)-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-(S)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-(R)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-9-[4-(1-methyl-1H-pyrrole-2-carbonyl)-piperazin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-6-oxo-9-[4-(2,3-dihydro-thiazole-4-carbonyl)-piperazin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-9-[4-(4-methyl-thiazole-5-carbonyl)-piperazin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-6-oxo-9-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-[4-(furan-2-carbonyl)-piperazin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-9-{4-[1-(2-morpholin-4-yl-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-piperazin-1-yl}-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-{4-[1-(3-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-piperazin-1-yl}3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,as well as their salts.
The compounds of the invention can be prepared by a method characterized in that a compound of formula (II):
in which R4, R′4, R5 and R7 are as defined above and R′6 has the values of R6 defined above or represents another group protecting the carboxylic function, is treated by a compound of formula (III):
in which R1, R2, R3 and R′3 are as previously defined, in the presence of a base, then, if appropriate, the protective groups present are eliminated and, if desired, the carboxy group is esterified by action of an alcohol, and the compound of formula (I) is salified.
The procedure is carried out preferably in a sealed chamber, in solution in the pyridine, at the reflux temperature of the latter. The base used is preferably a tertiary amine, for example triethylamine, N-methyl morpholine or also DBU. When R′6 represents a protective group, it can in particular be a (C1-C6) alkyl, a (C2-C6) alkenyl, or a (C7-C14) arylalkyl. After final elimination of the protective group R′6, the acid obtained can if desired be re-esterified to form a compound in which R6 is different from hydrogen.
Protection of the heterocyclic nitrogen and the amines may be necessary and is carried out in particular, according to circumstances, in the form of benzyl or trityl derivatives, in the form of carbamates, in particular allyl, benzyl, phenyl or tertbutyl, or also in the form of silyl derivatives such as dimethyl, trimethyl, triphenyl tertbutyl or also diphenyl tertbutyl-silyl derivatives. Deprotection is carried out, according to the nature of the protective group, by sodium or lithium in liquid ammonia, by hydrogenolysis or using soluble palladium 0 complexes, by action of an acid, or by action of tetrabutylammonium fluoride or strong bases such as sodium hydride or potassium tert-butylate. These reactions are well known to a person skilled in the art and well described for example by T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York. Illustrations are provided below in the experimental part.
The compounds of formula (II) are generally known and can be prepared by the methods described in U.S. Pat. No. 4,801,584. The compound of formula (II) in which R4 and/or R′4 represent/s an alkyl radical optionally substituted by 1 to 3 halogens can be prepared from a compound of formula (II) in which R4 and R′4 represent a hydrogen, which is hot-treated with an alkaline aqueous base, then neutralized, in order to obtain the compound of formula (IV):
in which R5, R′6 and R7 are defined as above, which is treated in dioxane at boiling point by a compound of formula (V)
in which R4 and R′4 are defined as above. The compound of formula (II) in which R5 represents a methyl radical substituted by 1 to 3 halogens can be prepared according to a method such as the one described in U.S. Pat. No. 4,801,584.
The compounds of formula (III) can be prepared by methods known to the skilled chemist and, for example, by those described in the following documents: Helv. Chem. Acta, 1951, 12, 34, 1544-1575; J. Med. Chem. 2004, 47, 25, 6218-6229; Bioorg. Med. Chem. 2006, 16, 20, 5462-5467; Tetrahedron 1992, 48, 23, 4985-4998; Tetrahedron Asymmetry 1993, 4, 11, 2389-2398; Tetrahedron Asymmetry 1996, 7, 9, 2739-2742; Tetrahedron Assymetry 1993, 7, 7, 1999-2006; Bioorg. Med. Chem. Letters 2004, 12, 1, 71-86; WO2006127694; U.S. Pat. No. 6,284,757; WO2006172831; WO2007/28654; U.S. Pat. Nos. 5,354,747; 5,576,314. Preparations of compounds of formula (III) are also provided below in the experimental part.
Typically, following compounds of formula (IIIa):
in which R3, R3′, Ra, Rb and Rb′ are defined as above, can be prepared from a compound of formula (IV):
which is treated by a strong reducer, preferentially LiAlH4, in an ethereal solvent such as diethyl ether or tetrahydrofuran, at reflux temperature.
Compounds of formula (IV) can themselves be prepared by heating a compound of formula (V):
in which R8 represents a (C1-C6) alkyl or a (C7-C14) arylalkyl group, in an appropriated solvent, preferentially an alcoholic solvent such as methanol or ethanol.
Compounds of formula (V) can be prepared by coupling the appropriated substituted proline of formula (VI), in which Ra, Rb and Rb′ are defined as above, with the corresponding amino ester of formula (VII) in which R3, R3′ and R8 are defined as above.

The conditions for the coupling reaction are those known in the art, and can employ conventional associations of coupling reagents used in peptidic chemistry such as HOBT, EDCl, in presence of a base such as diisopropylethylamine or triethylamine and in a solvent such as dimethylformamide. Compounds of formula (III)/(IIIa), wherein R1 and R2 form a 5 or 6 membered carbon cycle are known and described for example in U.S. Pat. No. 5,354,257 or 5,576,314 and/or are commercially available. As stated above, the compounds of formula (I) can be in the form of enantiomers or mixtures of enantiomers essentially at position 9 of the ring. The compounds of formula (I) are obtained without racemization and, as a result, enantiomers can be obtained by using the corresponding enantiomer of the compound of formula (III) and/or (IV).
The compounds according to the invention, and more particularly those wherein R1 and R2 form an optionally substituted 5 or 6 membered carbon cycle, have remarkable antibacterial properties and these properties manifest themselves over a wide spectrum of gram (−) bacteria, but also a wide spectrum of gram (+). This balanced antibacterial activity distinguishes them from compounds of the prior art, for example marbofloxacine or also ofloxacine, and means that they are particularly indicated for use as medicaments in human medicine, but also in veterinary medicine for which there is a need for compounds which are particularly active in relation to these bacteria. Thus the above compounds are active in particular on gram (+) bacteria such as Streptococcus uberis or Staphylococcus aureus, but also Mycoplasma bovis or bovirhinis, or Clostridium perfringens or Enterococcus faecalis, while still being remarkably active on gram (−) bacteria such as Mannheimia haemolytica, Bordetella bronchiseptica, Escherichia coli or Pseudomonas aeruginosa. 
These properties make said compounds, as well as their salts with pharmaceutically acceptable acids and bases, suitable for use as medicaments in the treatment of conditions with susceptible germs and in particular those involving staphylococci, such as staphylococcal septicaemia, malignant staphylococcal infection of the face or skin, pyoderma, septic or suppurating sores, anthrax, phlegmon, erysipeles, primitive or post-influenzal acute staphylococcal infections, bronchial pneumonia, pulmonary suppurations. The compounds can also be used as medicaments in the treatment of colibacilloses and associated infections, in Proteus, Klebsiella, Pseudomonas or also Salmonella infections and in other conditions caused by gram (−) bacteria.
A further subject of the present invention is therefore the use as medicaments, and in particular as antibiotic medicaments, of the compounds of formula (I) as defined above, as well as their salts with pharmaceutically acceptable acids and bases. More particularly, a subject of the invention is the use, as medicaments, of the preferred compounds of formula (I) defined above, in particular including the compounds of formula (I1) defined above and the compounds listed below:    8-Fluoro-3-methyl-9-(octahydro-pyrido[1,2-a]pyrazin-2-yl)-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-(S)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-(R)-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-9-[4-(1-methyl-1H-pyrrole-2-carbonyl)-piperazin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-6-oxo-9-[4-(2,3-dihydro-thiazole-4-carbonyl)-piperazin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-9-[4-(4-methyl-thiazole-5-carbonyl)-piperazin-1-yl]-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-6-oxo-9-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-[4-(furan-2-carbonyl)-piperazin-1-yl]-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-3-methyl-9-{4-[1-(2-morpholin-4-yl-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-piperazin-1-yl}-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,    8-Fluoro-9-{4-[1-(3-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-piperazin-1-yl}-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid,as well as their pharmaceutically acceptable salts.
A subject of the invention is also the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments according to the invention as defined above. These compositions can be administered by oral, rectal, parenteral, in particular intramuscular route, by respiratory route or by local route in topical application to the skin and mucous membranes.
The compositions according to the invention can be solid or liquid and be present in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the customary methods. The active ingredients can be incorporated in same, using excipients which are customarily used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa buffer, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives. These compositions can in particular be present in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example, non-pyrogenic sterile water. The dose administered varies according to the condition treated, the patient in question, the administration route and the product envisaged. It can, for example, be comprised between 0.25 g and 10 g per day, by oral route in humans, with the product described in example 1 or also comprised between 0.25 g and 10 g per day by intramuscular or intravenous route.